1. Field of the Invention
The present application relates to improved processes for the preparation of triazinyl-substituted oxindoles and their use as intermediates for the synthesis of fine chemicals and of active ingredients in the field of agriculture.
2. Description of Related Art
Oxindoles substituted in the 3 position are an important structural motif among a series of natural substances and pharmaceutically effective substances. Some of these compounds exhibit biological activity against various pathogens and have e.g. antitumor or anti-HIV properties (Ding et al., J. Med. Chem. 2006, 49, 3432; Jiang et al., Bioorg. Med. Chem. Lett. 2006, 16, 2105).
A further subgroup of the oxindoles substituted heteroaromatically in the 3 position are the 3-triazinyloxindoles (3-(1,3,5-triazin-2-yl)-1,3-dihydro-2H-indol-2-one. The preparation of these compounds, referred to by the trivial name of “3-triazinyloxindoles”, is the subject of the present invention.
It is known that a hydrogen bonded to an aromatic, heteroaromatic or to an aliphatic carbon backbone can be exchanged for functional substituents which may likewise be aromatic, heteroaromatic or aliphatic.
In this connection, it is interesting that the reaction conditions for the substitution of the hydrogen in the 3 position of oxindoles are different depending on the nature of the substituents. Accordingly, the reaction conditions for the exchange for aliphatic, aromatic and heteroaromatic radicals have been researched and developed independently of one another.
Standard reactions of the substitution of oxindoles in the 3 position include the exchange of hydrogen for aliphatic substituents (Science of Synthesis, 10 (2000), p. 600).
The exchange for aromatic substituents in the presence of palladium was described by Taylor et al. (J. Am. Chem. Soc., 2009, 131, 9900-9901), and also by Altman et al. (J. Am. Chem. Soc. 2008, 130 (29), 9613-9620), and also by Durbin et al. (Org. Lett., 2008, 10 (7), 1413-1415).
The synthesis of substituted oxindoles in which the hydrogen have been exchanged for heteroaromatic 6-ring substituents has likewise been described. By way of example, mention is made here of the substitution in the 3 position of N-methyl-oxindole with a substituted pyridazine (Shen et al., Org. Lett., 2006, 8, 1447-1450), the preparation of substituted 3-(quinazolin-4-yl)oxindoles (U.S. Pat. No. 6,265,411), the substitution in the 3 position of oxindole with substituted quinazolines over a solid phase (Hennequin et al., Tetrahedron Lett., 1999, 40, 3881-3884), the substitution with substituted pyridines or pyridine N-oxides (e.g. US 2009/291982, WO 2007/89193, WO 2005/27823, WO 2003/82853), the preparation of substituted 3-(pyrimidin-4-yl)oxindoles (WO 2006/136606, WO 2003/82853, US 2007/281949) or the preparation of substituted 3-(2H-pyrazolo[3,4-d]pyrimidin-4-yl)oxindoles (US 2007/281949).
According to Scheme 1,3-triazinyloxindoles can be obtained by exchanging a hydrogen atom in the 3 position of an optionally substituted oxindole (1) for an optionally substituted triazine (2) which carries a suitable leaving group X, in the presence of a “suitable” base.

In this connection, it is known that the step of deprotonation of the oxindole that is important for the exchange of the hydrogen can be influenced in a targeted manner through the choice of substituent R3.
A common feature of the reactions disclosed in the aforementioned prior art is that the oxindole used is firstly deprotonated with a strong base and then the heterocyclic component, typically as chlorine compound, is added.
For the purposes of the deprotonation, in the prior art, strong, water-sensitive bases, such as sodium hexamethyldisilazane or lithium diisopropylamide (LDA), sodium hydride or lithium hydride, are used.
Disadvantageously, the use of the bases sodium hydride and lithium hydride leads to the formation of equimolar amounts of elemental hydrogen. Moreover, the solvents used in connection with these bases have to be laboriously dried prior to being used.
An analogous coupling—analogous to the coupling of oxindoles with quinolines described in WO 2005/061519, in which quinoline N-oxides are used in the presence of acidic anhydride—with triazines of formula (2) is not known.
Scheme 2 summarizes a known process for the preparation of substituted 3-triazinyloxindoles. These are characterized in that they carry nitrogen substituent on the triazine ring. The synthesis is disclosed in US 2004/116388, WO 2002/083654 and WO 2001/025220.

In the reaction according to Scheme 2, a substituted 4-chloro-N-phenyl-1,3,5-triazine-2-amine was used as triazine-containing component. The reaction was carried out by deprotonation of the oxindole used in DMF/THF with sodium hydride, followed by the addition of the triazine component and subsequent stirring of the reaction mixture at 80° C.
Disadvantageously, the achieved yields for this known synthesis are only 2.5%, or 7% for the oxindoles unsubstituted on the nitrogen (R2═H), and 29% for N-methyl-oxindole (R2=Me).
As well as the very low yields, the disadvantages of the described process are also the use of strong bases such as sodium hydride, which lead to the formation of equimolar amounts of elemental hydrogen, which are difficult to handle industrially. Consequently, the described process is not a viable solution for the industrial scale.
In the process, described in US 2004/116388 for the compound with the number 380, for the preparation of substituted 3-triazinyloxindoles, only 0.4 equivalents of the triazine component are used per equivalent of the oxindole component. Based on the oxindole component, this can lead merely to a maximum theoretical yield of 40%. An increase in the yield can be achieved through the use of an excess of oxindole. Since the oxindole component can, depending on the substitution pattern, be the somewhat more valuable starting material, this reaction procedure using a 2.5-fold excess of oxindole on an industrial scale is to be regarded as disadvantageous.
It has already been indicated that the reaction conditions for the exchange of the hydrogen in the 3 position of oxindoles for aliphatic, aromatic and heteroaromatic substituents had to be established in each case independently of one another because the type of substituents to be introduced can heavily influence the reaction.
The same appears to apply in turn to the further branching, i.e. the further substitution of these substituents, in particular to the further substitution of the heteroaromatic substituents.
Thus, the prior art describes no industrially suitable synthesis of 3-triazinyloxindoles which carry alkyl or alkoxy substituents on the triazine ring.
The use of the hitherto known preparation processes in the synthesis of 3-triazinyloxindoles which carry alkyl or alkoxy substituents on the triazine ring does not produce satisfactory results on an industrial scale.
For comparison purposes, the conditions, described in the document US 2004/116388, in the reaction of 7-fluoro-1,3-dihydro-2H-indol-2-one (example 1 Variant F), or 1,3-dihydro-2H-indol-2-one (Example 2 Variant B) with 2-chloro-4,6-dimethoxy-1,3,5-triazine were used.
In this connection, it was found that the yields achieved, in each case based on the oxindole component, are only 39% (Example 1 Variant F), or only 34% (Example 2 Variant B). If these conditions are used in the reaction of the starting materials in an industrially advantageous ratio, namely 1 equivalent of the oxindole component with 1.2 equivalents of the triazine component, then the yields achieved are 39% (Example 1 Variant G) or 30% (Example 2 Variant C).
In Organic Letters (2010) 2306-2309, in the arylation reactions described in Table 4, the starting material used in each case is 3-phenyloxindole, i.e. an oxindole which carries a phenyl substituent in the 3 position. This 3-phenyloxindole is arylated with electron-poor chlorobenzene derivatives and 5-halooxazoles in the presence of caesium carbonate in the 3 position.
As is known, the acidity of methyl groups or methylene groups is usually greatly increased by exchanging a hydrogen substituent for a phenyl substituent. This leads to a reduced pKa value of the remaining hydrogen substituent(s) on methyl group or methylene group by several orders of magnitude.
In a series of publications, corresponding examples can be found in which pKa values of organic or inorganic compounds in water or in organic solvents such as dimethyl sulfoxide are described. The pKa values in organic solvents were either measured directly or extrapolated by means of other methods. For example, in Acc. Chem. Res. 1988, 21, 456 in Table II, for 4-methylpyridine, a pKa value of 35 (extrapolated for DMSO) and for 4-benzylpyridine a pKa value of 26.7 (in DMSO) is given. Likewise in Acc. Chem. Res. 1988, 21, 456 in Table II, for (methylsulfanyl)benzene, a pKa value of 42 (extrapolated for DMSO) is given, for (benzylsulfanyl)benzene, a pKa value of 30.8 (in DMSO) is given, and for diphenylmethyl phenylsulfide, a pKa value of 26.8 (in DMSO) is given. For oxindole, in Acc. Chem. Res. 1988, 21, 456 in Table II, a pKa value of 18.2 (in DMSO) is given.
From the examples given, the increase in acidity of methyl groups or methylene groups by several orders of magnitude as a result of exchanging a hydrogen substituent for a phenylsubstituent becomes very evident.
In the examples of the present application, the starting materials used were only oxindoles which carry two hydrogen atoms in the 3 position. In Organic Letters (2010) 2306-2309, by contrast, 3-phenyloxindoles are used as starting materials. The starting materials therefore differ in their acidity. Oxindoles which carry two hydrogen atoms in the 3 position are less acidic than the 3-phenyloxindole used in Organic Letters (2010) 2306-2309 in the reactions of Table 4.
It is therefore not surprising that in the literature examples in which arylation reactions on oxindoles unsubstituted in the 3 position are described, strong bases such as sodium hydride are used. The fact that also for oxindoles which carry a substituent in the 3 position which reduces the acidity in non-aqueous solvents by several orders of magnitude, relatively weak bases such as caesium carbonate can be used for the deprotonation was to be expected by the person skilled in the art and was confirmed in Organic Letters (2010) 2306-2309.
However, it is surprising to the person skilled in the art that, according to the teaching of the invention, an arylation reaction on oxindoles unsubstituted in the 3 position (oxindoles which have two hydrogens in the 3 position) is possible, contrary to expectations, even with relatively weak bases such as potassium carbonate or sodium hydroxide in good yields.
In order to test the applicability of the conditions described in Organic Letters (2010) 2306 (Supplement page S-12 General Procedure) for the arylation of 3-aryloxindoles with electron-poor chlorobenzene derivatives and 5-halooxazoles (Table 4 in Organic Letters (2010) 2306) also when using chlorotriazines, 3-phenyl-1,3-dihydro-2H-indol-2-one was reacted with 2-chloro-4,6-dimethoxy-1,3,5-triazine in the presence of caesium carbonate in N,N-dimethylformamide (see Example 10). Since the reaction proceeded very rapidly even at room temperature, an elevated temperature and extended reaction time were dispensed with. The product present in the reaction mixture was purified by column chromatography. Structural elucidation by means of 2D-NMR demonstrates that the product obtained, however, is not the desired product arylated in the 3 position (3-(4,6-dimethoxy-1,3,5-triazin-2-yl)-3-phenyl-1,3-dihydro-2H-indol-2-one), but the O-arylated product (2-[(4,6-dimethyoxy-1,3,5-triazin-2-yl)oxy]-3-phenyl-1H-indole).
Afterwards, again for comparison purposes, the conditions for the arylation described in Organic Letters (2010) 2306 (Supplement page S-12 General Procedure) were likewise applied while using chlorotriazines, and specifically for the arylation of an oxindole unsubstituted in the 3 position. For this purpose, 7-fluoro-1,3-dihydro-2H-indol-2-one was reacted with 2-chloro-4,6-dimethoxy-1,3,5-triazine in the presence of caesium carbonate in N,N-dimethylformamide (Example 1 variant H). However, the title compound arylated in the 3 position with only 22% yield is obtained as reaction product. As main products, polyarylated products were obtained in the isolated solid and also in the concentrated mother liquor. It was also shown, by means of HPLC analysis, that the oxindole used as starting material had not completely fully reacted.
Consequently, the process described in Organic Letters (2010) 2306 (Supplement page S-12 General Procedure) is not suitable for producing 3-triazinyloxindoles on an industrial scale, at least when 2-chloro-4,6-dimethoxy-1,3,5-triazine is used as arylating reagent.